Janus kinase (JAK) signaling pathway, discovered in interferon-induced receptor mediated gene expression, has been shown to be a common signaling pathway used by many cytokines and growth factors. See, e.g., Darnell et al., Science 1994, 264, 1415-1421; Ihle, Nature 1995, 377, 591-594; Leonard et al., Annu. Rev. Immunol. 1998, 16, 293-322. The mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). JAKs range in size from 120 to 140 kDa and contain seven conserved JAK homology (JH) domains, which define this kinase super family. See, e.g., Gadina et al., Curr. Opin. Immunol. 2001, 13, 363-373.
Binding of a cytokine to a cell surface receptor results in receptor dimerization and subsequent activation/phosphorylation of JAK tyrosine kinases that are constitutively associated with the receptor. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for a family of latent cytoplasmic transcription factors known as Signal Transducers and Activators of Transcription (STATS). STATS are phosphorylated by JAKs, dimerize, and then translocate to the nucleus where they bind specific DNA elements and activate gene transcription. See, e.g., Villarino et al., J. Immunol. 2015, 194, 21-27.
The JAKs are activated by a wide range of cytokines that play essential roles in immune function, inflammation, and hematopoiesis. See, e.g., Hofmann et al., Curr. Opin. Allergy Clin. Immunol. 2002, 2, 495-506; O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328. JAK1 and JAK3 can be activated by a member of the γ common (γc) subfamily, namely, interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; however, these cytokines never activate JAK2 or TYK2. The importance of these cytokines to the immune system is highlighted by observation of severe combined immunodeficiency when loss-of-function mutations occur in these cytokines or in JAK3. Another large subfamily of cytokines that shares the glycoprotein 130 (gp130) signal transducing subunit includes IL-6, IL-11, IL-27, and several other cytokines. The signaling of these cytokines always involves JAK1 activation, and JAK2 and TYK2 are also consistently engaged. IL-6 has been implicated in immune response, and excessive stimulation of this pathway is linked to various autoimmune and chronic inflammatory conditions. Numerous homodimeric receptors for erythropoietin (EPO), prolactin, thrombopoietin, and growth hormone are known to activate JAKs. The EPO pathway activates JAK2 exclusively and is essential to red blood cell formation or erythropoiesis.
Each JAK isoform can be employed by multiple cytokine pathways and by extension, the biological activities of many cytokines can be modulated by inhibition of a single or multiple JAKs. See, e.g., O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328. Inhibition of JAK can be useful for preventing, inhibiting, or treating the progression or onset of various diseases and disorders, including hyper-proliferative disorders and cancer such as leukemia and lymphomas, immunological and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis. See, e.g., Quintás-Cardama et al., Nat. Rev. Drug Discov. 2011, 10, 127-140; O'Shea et al., Nat. Rev. Rheumatol. 2013, 9, 173-182; O'Shea et al., Annu. Rev. Med. 2015, 66, 311-328.